One of the primary functions of the proximal tubule is to absorb NaCl. Formate, PTH and angiotensin II are potent regulators of proximal tubule NaCl transport. Regulation of NaCl transport by formate in the proximal straight tubule is currently believed to be mediated by apical Cl-/formate exchange coupled to Na+/H+ exchange with apical formic acid recycling. However, the transport properties of the rabbit proximal straight tubule characterized by their laboratory do not support this model. In the rabbit superficial S2 proximal straight tubule, apical Cl-/base exchange occurs in the absence of exogenous formate and bicarbonate, and is stimulated by Na+ removal. The data suggest that this transporter functions in a Cl/OH- mode. Na+ removal appears to regulate apical Cl-/base exchange via a change in intracellular Ca2+. S2 tubule formate production and blood formate concentration are too low to permit significant apical formic recycling yet it is generally agreed that luminal formate stimulates the transepithelial NaCl absorption. In this proposal, the data by the principal investigator demonstrates that luminal formate stimulates the apical Na+/H+ exchange activity directly. The principal investigator also shows evidence that PTH and AII regulate apical/basolateral anion exchange and Cl- transport in the proximal straight tubule. The following hypotheses will be tested in this proposal: 1) apical NaCl uptake is mediated predominantly by Na+/H+ exchange coupled to Cl-/base exchange; 2) Na+ removal regulates apical Cl-/base exchange through an increase in intracellular Ca2+ via a calmodulin-dependent mechanism; 3) Luminal formate increases transepithelial NaCl transport by stimulating the apical Na+/H+ exchange and not via formate-dependent Cl-/base exchange; 4) Basolateral formate decreases transepithelial NaCl transport by stimulating the basolateral Na+/H+ exchange; and 5) PTH and AII regulate apical and basolateral anion exchange and Cl- transport in the proximal tubule.